# Mechanism of Activation of eEF-2K, an Energy and Nutrient Sensor

> **NIH NIH R01** · UNIVERSITY OF TEXAS AT AUSTIN · 2020 · $396,783

## Abstract

ABSTRACT
Protein synthesis (translation) constitutes one of the most fundamental of all cellular processes. The balance
between protein synthesis and protein degradation is critical in maintaining cellular homeostasis. Translation
is one of the most energy consumptive processes in a cell, accounting for as much as 30% of the energy usage in
a eukaryotic cell, making its tight regulation a necessity. Eukaryotic elongation factor 2 kinase (eEF-2K), a
unique member of the α-kinase family, is a key regulator of the elongation phase of translation. eEF-2K
phosphorylates and inactivates elongation factor 2 (eEF-2), leading to a reduction in global translation rates on
one hand and differential translation of certain proteins on the other. The activity of eEF-2K is dependent on
calmodulin, and is subject to complex regulation by calcium ions and phosphorylation . While there is
accumulating evidence that the dysregulation of eEF-2K activity is involved in several disease states (e.g.
Alzheimer's disease, depression, and a variety of cancers), a detailed mechanistic understanding of eEF-2K
activation and regulation is lacking. Our long-term goal is to precisely define the mechanisms by which eEF-2K
is activated and regulated; such information is critical to understanding its contributions to both normal
cellular processes and in the etiology and progression of disease states. Toward this goal, we recently identified
calmodulin-stimulated autophosphorylation on a specific residue, T348, as being the key step in the activation
of eEF-2K. Our objective in the present proposal is to describe the structural and biochemical mechanisms of
eEF-2K activation by calmodulin and the roles of calcium and phosphorylation at a regulatory site, S500, in
modulating this process. We will achieve this goal through a multi-faceted and collaborative approach that
encompasses enzymological, kinetic, solution-state nuclear magnetic resonance and cell-biological techniques.
Our central hypothesis is that T348 autophosphorylation and activation of eEF-2K is dependent on
calmodulin binding. Calcium ions and S500 phosphorylation play overlapping roles but utilize distinct
mechanisms in regulating the calmodulin sensitivity of eEF-2K and thereby its activation. We expect our
analyses will provide the basis for a thorough mechanistic understanding of how eEF-2K integrates these two
disparate signals that regulate its activity. Such a detailed picture of eEF-2K regulation is critical for elucidating
its contribution to a variety of fundamental cellular process and its deregulation in a variety of disease states.

## Key facts

- **NIH application ID:** 9952382
- **Project number:** 5R01GM123252-04
- **Recipient organization:** UNIVERSITY OF TEXAS AT AUSTIN
- **Principal Investigator:** Kevin N Dalby
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $396,783
- **Award type:** 5
- **Project period:** 2017-09-15 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9952382

## Citation

> US National Institutes of Health, RePORTER application 9952382, Mechanism of Activation of eEF-2K, an Energy and Nutrient Sensor (5R01GM123252-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9952382. Licensed CC0.

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